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Biomedical subjects

J J Fox

Publications and source records attributed to J J Fox.

At least 19 recordsLinked to original sources
PubMed1998

Dipyridamole potentiates pulmonary vasodilation induced by acetylcholine and nitric oxide in the ovine fetus.

Nitric oxide (NO) modulates pulmonary vascular resistance (PVR) in the normal fetus by increasing the cyclic guanosine 3',5'-monophosphate (cGMP) content of pulmonary vascular smooth muscle cells. Although several vasodilator stimuli, including acetylcholine, decrease fetal PVR through the release of endogenous NO, fetal pulmonary vasodilation is often transient despite prolonged treatment. Because cGMP is hydrolyzed and inactivated by cGMP-specific (type 5) phosphodiesterases (PDE5), we hypothesized that PDE5 activity contributes to high fetal PVR and limits the capability of the fetal pulmonary circulation to dilate or sustain vasodilation in response to cGMP-dependent stimuli. To test this hypothesis, we studied the hemodynamic effects of dipyridamole in 19 late-gestation fetal lambs. To determine whether dipyridamole-induced vasodilation is dependent upon basal NO release, we measured the response to dipyridamole before and after pretreatment with the NO synthase antagonist nitro-L-arginine (L-NA) in five fetal lambs. L-NA completely blocked dipyridamole-induced pulmonary vasodilation. To evaluate the effect of dipyridamole on pulmonary vasodilation due to the stimulated release of NO, we studied effects of prolonged intrapulmonary acetylcholine infusions, with and without concomitant administration of low-dose dipyridamole, in six fetal lambs. During prolonged (2-h) infusions, acetylcholine and dipyridamole individually caused transient pulmonary vasodilation. When administered together, pulmonary vasodilation was of greater magnitude and was sustained for the entire study period. To determine the effects of dipyridamole on endothelium-independent pulmonary vasodilation, we investigated the hemodynamic effects of inhaled NO (5 and 20 ppm) alone and in combination with dipyridamole during mechanical ventilation with low FlO2. The combination of dipyridamole with inhaled NO resulted in a greater degree of pulmonary vasodilation than that achieved with inhaled NO alone. We conclude that dipyridamole-induced pulmonary vasodilation is dependent on endogenous (basal) NO production and that dipyridamole potentiates vasodilator responses to endothelium-dependent and -independent dilators in the ovine fetal pulmonary circulation. We speculate that PDES activity opposes vasodilation and maintains high PVR in the normal fetal lung.

Acetylcholine↗
PubMed1996

Role of nitric oxide and cGMP system in regulation of ductus arteriosus tone in ovine fetus.

Although endogenous nitric oxide (NO) modulates basal tone in the fetal pulmonary and systemic circulations, little is known about its role in regulating ductus arteriosus (DA) tone. Immunostaining of DA tissue from late-gestation fetal lambs demonstrated strong staining for endothelial NO synthase (eNOS) in DA endothelium. To study the physiological role of the NO and guanosine 3',5'-cyclic monophosphate (cGMP) system in the DA in vivo, we measured the hemodynamic effects of NG-nitro-L-arginine (L-NNA; 30 mg), a NOS inhibitor, methylene blue (40 mg), a guanylate cyclase inhibitor, and indomethacin (0.8 mg), a cyclooxygenase inhibitor, in 10 chronically prepared late-gestation fetal lambs. L-NNA increased main pulmonary artery (MPA) and aortic pressures (P < 0.05 vs. baseline) but did not change the pressure gradient between the MPA and the aorta. L-NNA caused a small decrease in DA flow and a slight rise in resistance across the DA. Methylene blue increased both MPA pressure and the pressure gradient between the MPA and the aorta from 0.3 +/- 0.2 (baseline) to 7.0 +/- 2.7 mmHg (P < 0.05). Indomethacin increased both MPA pressure and the pressure gradient between the MPA and the aorta from 1.1 +/- 0.4 (baseline) to 6.3 +/- 1.5 mmHg (P < 0.05) after 40 min. Indomethacin decreased DA flow and increased DA resistance. We conclude that eNOS is in fetal DA endothelial cells and that NOS inhibition causes constriction of the DA in vivo. DA constriction after NOS inhibition is minimal, especially in comparison with cyclooxygenase inhibition. Methylene blue also constricts the DA, suggesting that guanylate cyclase activity contributes to DA relaxation. We speculate that, although the NO and cGMP system modulates DA tone, prostaglandins may play a greater role.

Animals↗
PubMed1996

Chronic intrauterine pulmonary hypertension alters endothelin receptor activity in the ovine fetal lung.

Although endothelin (ET) contributes to the regulation of pulmonary vascular tone in the normal fetus, little is known about its role in pulmonary hypertension in the perinatal period. To examine the role of the ETB receptor in the normal ovine fetal lung, we studied the hemodynamic effects of ET-3 (a selective ETB receptor agonist) before and after RES-701 (a selective ETB receptor antagonist). RES-701 (10 mu g/min for 10 min) did not change basal pulmonary tone and blocked pulmonary vasodilation to ET-3 (500 ng/min for 10 min). To examine the effects of experimental perinatal pulmonary hypertension on activity of the ETA and ETB receptors, we studied the hemodynamic effects of ET-3, ET-1 (a nonselective ETA and ETB receptor agonist), and BQ 123 (a selective ETA receptor antagonist) in 12 chronically prepared late gestation fetal lambs after partial ligation of the ductus arteriosus. Serial changes in the pulmonary vascular effects of these agents were measured early (1-3 d) and late (7-10 d) after partial ductus arteriosus ligation. Left lung total pulmonary resistance in the normal late-gestation fetus was 0.62 +/- 0.01 mm Hg/ml/min (n = 4). After partial ductus arteriosus ligation, total pulmonary resistance increased to 1.2 +/- 0.3 (early; p < 0.05 versus normal), and progressively rose to 1.9 +/- 0.2 mm Hg/ml/min (late; p < 0.05 versus early). Intrapulmonary infusion of ET-3 (500 ng/min for 10 min) increased pulmonary blood flow from 94 +/- 11 to 183 +/- 17 mL/min in the normal fetus, but had no effect during late pulmonary hypertension. Infusions of ET-1 (50 ng/min for 30 min) caused transient pulmonary vasodilation followed by vasoconstriction during early pulmonary hypertension. During late pulmonary hypertension, however, infusion of ET-1 caused predominantly vasoconstriction. Pulmonary vasodilation to BQ 123 (100 mu g/min for 10 min) was greater during late than early pulmonary hypertension (43 versus 21%; p < 0.05). After 10 d of ductus arteriosus ligation, immunoreactive ET-1 content in whole lung tissue was 3-fold higher in hypertensive (n = 7) than control (n = 10) lungs (p < 0.05). We conclude that the ETB receptor contributes little to regulation of basal vascular tone in the normal ovine fetal lung and that chronic intrauterine pulmonary hypertension causes the loss of ETB-mediated vasodilation, progressive ETA-mediated vasoconstriction, and increased lung ET-1 content. We speculate that diminished ETB receptor-mediated vasodilation in combination with enhanced ETA receptor-mediated vasoconstriction and increased ET-1 production contributes to high pulmonary vascular resistance in perinatal pulmonary hypertension.

Animals↗
PubMed1995

Dipyridamole, a cGMP phosphodiesterase inhibitor, causes pulmonary vasodilation in the ovine fetus.

Endogenous nitric oxide (NO) modulates fetal pulmonary vascular tone by stimulating guanosine 3',5'-cyclic monophosphate (cGMP) production in vascular smooth muscle. Because cGMP is hydrolyzed and inactivated by phosphodiesterase enzymes, we evaluated the hemodynamic effects of two cGMP-specific phosphodiesterase (PDE5) inhibitors, dipyridamole and zaprinast, in the near-term chronically prepared ovine fetus. Brief (10 min) intrapulmonary infusions of dipyridamole caused dose-dependent increases in left pulmonary artery flow and decreases in left pulmonary arterial resistance that persisted for > 40 min after termination of the infusion. Prolonged (2 h) infusions of dipyridamole caused sustained pulmonary vasodilation throughout the infusion period. To compare the hemodynamic effects of dipyridamole with the PDE5 antagonist zaprinast, we studied the responses to equimolar doses of both agents in four fetuses. Zaprinast caused dose-dependent pulmonary vasodilation that was equivalent to that noted with equimolar doses of dipyridamole. To determine whether adenosine is involved with dipyridamole-induced pulmonary vasodilation, we compared the hemodynamic response to dipyridamole before and after administration of the potent adenosine receptor (P1) antagonist 8-phenyltheophylline (8-PT). Pretreatment with 8-PT markedly attenuated adenosine-induced pulmonary vasodilation but had no effect on the hemodynamic response to dipyridamole. We conclude that cGMP-specific phosphodiesterase activity is important in regulating fetal pulmonary vascular tone. In addition, dipyridamole administration causes dose-dependent pulmonary vasodilation that is equivalent to zaprinast and not primarily due to its effects on adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1993

Assessing and enhancing generalization and social validity of social-skills interventions with children and adolescents.

Generalization and social validity are necessary aspects of any applied behavior analytic endeavor. They are especially critical to social-skills training research and practice. Investigators have demonstrated the effectiveness of various learning theory-based interventions in teaching social skills to and increasing peer interactions of children with and without disabilities. However, development of a technology for reliably transferring these changes across different situations or ensuring their persistence over time has proven to be more problematic. From both a conceptual and empirical standpoint, this article reviews progress in and barriers to assessing and enhancing generality of social behavior change and its relationship to social validity. If progress is to be made, then it will be necessary to (a) distinguish between generalization and generality in developing and evaluating social-skills interventions; (b) expand the concept of social validity to give more emphasis to objective measurement of social skills, interventions, and outcomes; and (c) pursue a systematic analysis of generality- and durability-programming tactics.

Adolescent↗
PubMed1992

Effects of 2'-fluorinated arabinosyl-pyrimidine nucleosides on duck hepatitis B virus DNA level in serum and liver of chronically infected ducks.

The 2'-fluorinated arabinosyl-pyrimidine nucleosides, 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) and 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU), are new antiviral compounds with in vitro inhibitory activity against the DNA polymerase of hepadnaviruses. Those compounds also induced permanent inhibition of viral replication in woodchucks chronically infected by woodchuck hepatitis virus. The effects of these antiviral compounds were assessed in ducks chronically infected by duck hepatitis B virus (DHBV). Following intraperitoneal administration for 5 days, FMAU (2 mg/kg/day) and FIAC (10 mg/kg/day) induced a transient decrease in DHBV replication, as shown by the decrease in both the serum and liver DHBV DNA level. After stopping therapy, DHBV replication rebounded immediately to the pretreatment level. The supercoiled form of liver viral DNA was found to be less affected by the therapy. By contrast, no obvious antiviral effect was observed with vidarabine monophosphate (ara-AMP) (80 mg/kg/day) therapy. No sign of toxicity was observed during the course of the treatment. These preliminary results confirmed in the DHBV model the higher efficacy of FIAC and FMAU as compared to ara-AMP. Pharmacokinetic studies are needed to explain the differences observed in viral replication in these 2 models of HBV infection.

Animals↗
PubMed1992

Evaluation of 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil in a rabbit model of herpetic keratitis.

The nucleoside analog 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5- ethyluracil (FEAU) was tested in a rabbit model of acute herpetic keratitis and its effectiveness compared with that of acyclovir (ACV). FEAU or ACV was applied topically 3 times daily, beginning 3 days post-HSV-1 inoculation and continued for a period of 7 days. FEAU at a concentration of 1% (w/v) or 3% ACV resulted in significant lessening of the severity of corneal lesions, conjunctivitis, iritis, and corneal clouding at 24 to 48 h after beginning chemotherapy. No toxic reaction was observed in any rabbit eyes treated with either FEAU or ACV. The duration of virus shedding into tear film and colonization of the trigeminal ganglia, however, were not reduced by either FEAU or ACV treatment begun 3 days post-inoculation. Fifty percent effective dose (ED50) of FEAU determinations performed on isolates from tear film and on the virus inoculum in secondary rabbit kidney cultures yielded a range of 4.6-7 microM, with two in vitro resistant isolates having ED50S of greater than or equal to 1500 microM of FEAU. Fifty percent cell growth inhibition for FEAU was 3000 microM at 72 h.

Acyclovir↗
PubMed1990

Effect of histocompatibility factors on pulmonary retention of indium-111-labeled granulocytes.

Granulocyte transfusions are associated with a number of side effects including febrile transfusion reactions and occasionally pulmonary infiltrates. There is evidence that the presence of preformed antibodies may be a cause of these complications. In this study, allogeneic 111Indium-labeled granulocytes were used to evaluate the pulmonary retention of radioactivity in alloimmunized and non-alloimmunized patients in an attempt to assess antibody effect on granulocyte migration. After injection of labeled allogeneic granulocytes into neutropenic patients, the ratios of lung to heart activity were calculated for the first 30 min of scanning. There was significantly greater retention of radioactivity from cells in the lungs of patients who were alloimmunized, having both lymphocytotoxic (anti-HLA) and leuko-agglutinating antibodies, compared to the activity in the lungs of non-alloimmunized patients (P less than .001) or of patients receiving autologous granulocytes (P less than .001). This study demonstrates that labeled, mismatched granulocytes may be retained in the lungs for a significantly longer time in patients with preformed antibodies. This implies that transfusion of large numbers of such mismatched granulocytes, i.e., granulocyte transfusions, may also be retained in the lungs of alloimmunized patients, which could lead to pulmonary compromise. Therefore, granulocyte transfusions from random donors should not be given to alloimmunized patients.

Blood Transfusion↗
PubMed1990

Inhibition of simian varicella virus infection of monkeys by 1-(2-deoxy-2- fluoro-1-beta-D-arabinofuranosyl)-5-ethyluracil (FEAU) and synergistic effects of combination with human recombinant interferon-beta.

1-(2-Deoxy-2-fluoro-1-beta-D-arabinofuranosyl)-5-ethyluracil (FEAU) has been shown to be a highly effective inhibitor of Simian varicella virus infection in African green monkeys. Administration of FEAU by either intravenous injection or gavage at doses as low as 1 mg/kg/day prevented the development of rash and reduced viremia. The effective dose could be further reduced to 0.2 mg/kg/day when administered in combination with a sub-effective dose of human recombinant interferon-beta. No evidence of toxicity was seen in monkeys treated for 10 days with FEAU doses of 10 mg/kg/day when they were monitored by hematology and clinical chemistry tests and by clinical observations.

Adenoviridae Infections↗
PubMed1990

Synthesis and anti-HIV-1 activity of 2'-"up"-fluoro analogues of active anti-AIDS nucleosides 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (DDC).

1-(3-Azido-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (6, F-AZT) and 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)cytosine (12, F-DDC) were synthesized from the potent antiherpes virus nucleosides 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (1, FMAU) and 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) in the hope that introduction of a 2-"up"-fluoro substituent might potentiate the anti-HIV activity of AZT and DDC. FMAU (1) was converted in three steps into 2,3'-anhydro-1-(2-fluoro-2-deoxy-5-O-trityl-beta-D-lyxofuranosyl)thymine (4), which when treated with NaN3 followed by detritylation afforded 6. F-DDC was prepared by two methods. Tritylation of FIAC followed by treatment of the product with thiocarbonyldimidazole afforded the 5'-O-trityl-3'-O-(imidazolyl)thiocarbonyl nucleoside 9. Upon radical reduction of 9 with Bu3SnH and AIBN, 5'-O-trityl-DDC 10 was obtained. Compound 10 was detritylated to give 12, which (when obtained by this procedure) resisted crystallization, but the diacetate 12' was obtained in crystalline form. Alternatively, FAC (14) was converted into N4,O5'-dibenzoyl derivative 15, which was treated with thiocarbonyldiimidazole. Reduction of 16 with Bu3SnH/AIBN followed by debenzoylation afforded 12, which was obtained in crystalline form. F-AZT did not exhibit any significant activity against the human immunodeficiency virus (HIV) in vitro. F-DDC, however, showed activity against HIV-1, but the therapeutic index is much inferior to that of AZT.

Antiviral Agents↗
PubMed1990

Inhibitory effects of 2'-fluorinated arabinosyl-pyrimidine nucleosides on woodchuck hepatitis virus replication in chronically infected woodchucks.

The treatment of woodchuck hepatitis virus infections with 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) and 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU), given intraperitoneally, caused complete and permanent decrease of serum virus endogenous DNA polymerase and viral DNA in all treated woodchucks but was associated with severe toxicity. By contrast 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (FEAU) induced a sustained, although less dramatic, decrease of viral replication without apparent toxic effect. FEAU was also effective when given orally. However, in both cases this inhibitory effect was transient.

Administration, Oral↗
PubMed1989

Nucleosides. CXXXV. Synthesis of some 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-9H-purines and their biological activities.

Seven purine nucleosides containing the 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl moiety were synthesized and tested for their antitumor activity. Direct condensation of 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (1) with N6-benzoyladenine in CH2Cl2 followed by saponification of the product afforded the adenine nucleoside (I, 2'-F-ara-A). Deamination of I with NaNO2 in HOAc gave the hypoxanthine analogue (II, 2'-F-ara-H). The 6-thiopurine nucleoside (III, 2'-F-ara-6MP) was prepared by condensation of 1 with 6-chloropurine by the mercury procedure followed by thiourea treatment and saponification of the product. Methylation of III gave the 6-SCH3 analogue (IV). Raney Ni desulfurization of III afforded the unsubstituted purine nucleoside (V, 2'-F-ara-P). Condensation of 1 with 2-acetamido-6-chloropurine by the silyl procedure afforded the protected 2-acetamido-6-chloropurine nucleoside which served as the precursor for both the guanine and 6-thioguanine nucleosides (VI, 2'-F-ara-G and VII, 2'-F-ara-TG, respectively). Thus, alkaline hydrolysis of the precursor gave VI. Thiourea treatment prior to alkaline hydrolysis gave VII. The new nucleoside, 2'-F-ara-G (VI) is found to be selectively toxic to human T-cell leukemia CCRF-CEM.

Animals↗
PubMed1988

Incorporation and metabolism of 2'-fluoro-5-substituted arabinosyl pyrimidines and their selective inhibition of viral DNA synthesis in herpes simplex virus type 1 (HSV-1)-infected and mock-infected Vero cells.

The incorporation and metabolism of 2'-fluoro-5-substituted arabinosyl pyrimidine analogs, and their selective inhibition of viral DNA synthesis in herpes simplex virus type 1 (HSV-1)-infected and mock-infected Vero cells were studied by HPLC and CsCl isopycnic density gradient analysis of isolated DNAs. The amounts of radiolabeled analogs incorporated as parent compound following 10 microM exposure for 4 h were 10-fold higher in HSV-1-infected vs mock-infected cells for 2'-fluoro-5-difluoromethyl-Ara-U (F2FMAU); 4.3-fold higher for 5-ethyl deoxyuridine (EdU); 2.6-fold higher for 2'-fluoro-5-methyl-Ara-U (FMAU) and 1.7-fold higher for dThd. For 2'-fluoro-5-ethyl-Ara-U (FEAU), 3.0 pmole of unchanged moiety was incorporated per 10(6) HSV-1-infected cells but no incorporation was detected in mock-infected cells. HPLC profiles showed that the percentages of radiolabeled analogs incorporated as parent compound in the DNA extracted from HSV-1-infected cells were 31.0% for F2FMAU, 99.6% for EdU, 83.5% for FEAU and 98.3% for FMAU; from mock-infected cells, they were 63.6% for F2FMAU, 96.7% for EdU, 97.3% for FMAU and no incorporation into DNA for FEAU was detected. CsCl density gradient analyses of isolated DNA showed that viral DNA synthesis was inhibited 98% by 10 microM FEAU, 92% by 10 microM F2FMAU, 90% by 2 microM FMAU and 80% by 50 microM EdU, whereas cellular DNA synthesis was inhibited by 53, 44, 61, 66 and 54%, respectively. We conclude that: (a) FEAU incorporation into host-cell DNA was not detectable but FEAU was selectively incorporated into HSV-infected cells; (b) FMAU and FEAU were metabolically stable; however, F2FMAU was extensively metabolized; (c) FEAU and F2FMAU were among the most selective inhibitors of HSV-1 DNA synthesis while allowing cellular DNA synthesis to continue.

Animals↗
PubMed1988

Effects of group socialization procedures on the social interactions of preschool children.

We investigated the effects of group socialization procedures on the social behavior of preschool children in two studies. Group socialization procedures consisted of teachers using antecedent and consequent events to promote social interaction during children's games. During intervention, teachers discussed friendship with the children and then prompted and praised child-child social responding within the context of games. Children's social behavior was assessed during two sessions, group game periods (i.e., intervention sessions) and nonintervention play periods (i.e., generalization sessions). In both studies, a multiple baseline design across two target children and peers in their respective group was used to evaluate the effects of group socialization procedures. During group game periods, after intervention, target children increased their rates of both prompted and unprompted social interactions with peers. Also, in nonintervention play periods, target children improved both the rate and the duration of their social responding with peers. Results indicated that group socialization procedures were a practical and effective method for improving young children's social interaction during both structured games and unstructured play activities.

Child, Preschool↗
PubMed1987

Increasing social interactions of severely handicapped autistic children.

A peer-initiation training procedure was implemented across multiple peer trainers to investigate social interactions between severely withdrawn autistic children and their nonhandicapped peers. For one subject, substantial increases in spontaneous interactions with training and nontraining peers occurred after the peer-initiation procedure was applied across two training exemplars. Spontaneous social interactions continued even after the training procedure was removed. Although experimental control was established with the second subject during training, spontaneous interactions during nontraining periods were primarily with training peers. The results contribute to an emerging data base on the social interactions of autistic and severely withdrawn handicapped children and on peer-initiation training procedures.

Autistic Disorder↗
PubMed1987

Cell differentiation effects of 2'-fluoro-1-beta-D-arabinofuranosyl pyrimidines in HL-60 cells.

A group of 2'-fluoro and 5-substituted arabinosyl pyrimidines and a group of base-substituted pseudoisocytidine analogs were evaluated for their capacity to induce differentiation in the human promyelocytic leukemia cell line, HL-60. These compounds were compared to 1-beta-D-arabinofuranosylcytosine (Ara-C) by monitoring: (1) inhibition of cell growth; (2) morphological maturation; (3) nitroblue tetrazolium (NBT) reduction; (4) expression of a myeloid differentiation antigen, Mo1; and (5) inhibition of colony formation. Exposure of logarithmically growing cells for 5 days to Ara-C, 2'-fluoro-Ara-C (FAC), 2'-fluoro-5-methyl-Ara-C (FMAC) and 2'-fluoro-5-ethyl-Ara-C (FEAC) resulted in cell growth inhibition at ED50 concentrations of 0.007, 0.11, 1.7 and 18 microM, and at cytostatic concentrations of 0.1, 0.5, 5.0 and 50 microM, respectively. These compounds induced granulocytic and monocytic maturation, reduction of NBT, increased expression of Mo1 antigen and a decrease or loss of both cell proliferation and colony formation in semisolid medium. There were few, if any, cell differentiation effects for the uracil nucleosides and pseudoisonucleosides tested. We found that Ara-C was the most cytotoxic of the compounds, and that when comparing absolute numbers of differentiated cells, i.e. percent of positive cells multiplied by the number of viable cells, FAC, FMAC and FEAC were superior to Ara-C inducing differentiation of HL-60 cells.

Antigens, Differentiation↗
PubMed1987

Nucleosides. 139. Synthesis and anticytomegalovirus and antiherpes simplex virus activity of 5'-modified analogues of 2'-fluoroarabinosylpyrimidine nucleosides.

In order to determine if modification of the 5'-position reduces or abolishes the antiviral activity of 2'-fluoro-5-iodo-ara-C (FIAC), 2'-fluoro-5-iodo-ara-U (FIAU), or 2'-fluoro-5-methyl-ara-U (FMAU) against human cytomegalovirus (HCMV) and herpes simplex virus (HSV), the 5'-deoxy, 5'-mercapto, and 5'-amino analogues of these nucleosides were prepared. 5'-Deoxy-FIAC and 5'-deoxy-FIAU were prepared by catalytic hydrogenation of 5'-iodo-FIAC and 5'-iodo-FIAU to 5'-deoxy-FAC and 5'-deoxy-FAU, respectively, followed by reiodination at C-5. Reduction of 5'-iodo-FMAU afforded 5'-deoxy-FMAU. These 5'-deoxy nucleosides were found to be inactive against HCMV, indicating that the conversion to 5'-phosphate by the cellular enzyme(s) is a requirement for antiviral activity against this virus. Other 5'-modified (NH2 and SH) analogues were also prepared from 5'-O-tosyl-FIAC and 5'-O-tosyl-FMAU. Treatment of these tosylates with LiN3 in DMF afforded the corresponding 5'-N3 products. Catalytic hydrogenation of 5'-N3-FMAU afforded 5'-NH2-FMAU, whereas 5'-NH2-FIAC was obtained by treatment of 5'-N3-FIAC with Ph3P in pyridine. 5'-Mercapto analogues were prepared by treatment of 5'-O-tosyl-3'-O-acetyl nucleosides with KSAc followed by deacetylation. 5'-NH2-FMAU was the only compound that showed good activity against HSV-1 and HSV-2 in vitro. However, this compound was less potent and had a lower therapeutic index than FMAU.

Animals↗